3-substituted-2,1-benzisothiazoline-2,2-dioxides

ABSTRACT

THE COMPOUNDS ARE 2,1-BENZISOTHIAZOLINE-2,2-DIOXIDES SUBSTITUTED IN THE 3 POSITION WHICH ARE USEFUL IN THE PREPARATION OF WOOD PRESERVATIVES, MOTH PROOFING AGENTS, PICKLING INHIBITORS AND AS PHARMACEUTICAL AGENTS, PARTICULARLY ANTIHYPERTENSIVE AGENTS. AMONG THE COMPOUNDS DISCLOSED ARE 1,3-DIMETHYL-3-(2&#39;&#39;-CARBOXYETHYL)-2,1-BENZISOTHIAZOLINE-2,2-DIOXIDE AND 1,3-DIMETHYL-3-(N-DIMETHYLAMINOETHYL) - 2&#39;&#39; - CARBAMYLETHYL)-2,1-BENZISOTHIAZOLINE2,2-DIOXIDE.

United States Patent 3,560,512 3SUBSTITUTED-2,1-BENZISOTHIAZOLINE-2,2-DIOXIDES Joseph A. Skorcz, Milwaukee, and John T. Suh and Claude I.Judd, Mequon, Wis., assignors to Colgate- Palmolive Company, New York,N.Y.

No Drawing. Continuation-impart of application Ser. No. 571,972, Aug.12, 1966. This application Nov. 14, 1967, Ser. No. 682,991

Int. Cl. C07d 91/06 US. Cl. 260-301 7 Claims ABSTRACT OF THE DISCLOSUREThe compounds are 2,1-benzisothiazoline-2,2-dioxides substituted in the3 position which are useful in the preparation of wood preservatives,moth proofing agents, pickling inhibitors and as pharmaceutical agents,particularly antihypertensive agents. Among the compounds disclosed are1,3-dimethyl-3-(2'-carboxyethyl)-2,l-benzisothiazoline-2,2-dioxide and1,3-dimethyl-3-[(N-dimethylaminoethyl) 2'carbamylethyl1-2,l-benzisothiazoline- 2,2-dioxide.

The present application is a continuation-in-part of our copendingapplication Ser. No. 571,972, filed Aug. 12, 1966, now abandoned.

SUMMARY OF THE INVENTION The present invention relates to novel3-substituted- 2,1 benzisothiazoline-2,2-dioxides, methods of preparingsuch compounds and compositions containing them.

DETAILED DESCRIPTION The novel compounds of the present invention may berepresented by the following formula:

N Y I in which X and Y are selected from hydrogen, lower alkyl of l to 4carbon atoms such as methyl, ethyl, propyl, isopropyl and butyl, loweralkoxy such as methoxy, ethoXy, propoxy and butoxy, an aralkoxy such asbenzyloxy, nitro, halogen such as bromo or chloro and trifluoromethyl; Ris a lower alkyl of 1 to 4 carbon atoms such as methyl, ethyl, propyl,isopropyl or butyl, a cycloalkyl of 3 to 7 carbon atoms such ascyclopropyl, cyclobutyl, cyclohexyl or cyclopentyl, a cycloalkyl-loweralkyl in which the cycloalkyl portion contains 3 to 7 carbon atoms suchas cyclopropyl methyl, cyclopentyl methyl, cyclopentyl ethyl andcyclohexyl methyl, phenyl, a nuclearsubstituted phenyl, particularly alower alkoxy-substituted phenyl such as p methoxyphenyl, or an aralkylof 7 to 13 carbon atoms, particularly a phenyl-lower alkyl such asbenzyl, phenethyl or phenylisopropyl; R is R, hydrogen or cyanoethyl; Bis a straight or branched chain alkylene of 1 to 6 carbon atoms such asmethylene, ethylene or propylene; Z is hydrogen, hydroxy, cyano,carboxy, carbamyl, -O-SO -phenyl, C(NOH)NH COR, and the ice groups CO Rand CONR R in which R is an alkyl of 1 to 8 carbon atoms or a tertiaryamino-lower alkyl such as dimethylaminoethyl or diethylaminopropyl, andR is not cyanoethyl. The compounds of the invention may be convenientlyprepared by employing a haloaniline such as o-chloroaniline orm-bromoaniline, or an N-substituted haloaniline such asN-phenyl-o-chloroaniline or N-p-methoxyphenyl-o-bromoaniline as thebasic starting material.

If an unsubstituted haloaniline is employed, it is first treated with analkylsulfonyl chloride to form a haloalkylsulfonanilide; thesulfonanilide is then treated with an alkyl ester such asdimethylsulfate, and a base such as p0- tassium hydroxide, to form anN-substituted-haloalkylsulfonanilide. The thus obtained sulfonanilide isthen treated with a nonparticipating strong base, for example, an alkaliamide such as sodium amide in an inert reaction medium such as liquidammonia, anhydrous ether, benzene or the like, to effect ring closure.

wherein D is a reactive halide, R, R X and Y are groups which do notinterfere with or partake in the reaction.

If an N-substituted haloaniline is employed as the starting material, itis first treated with an alkylsulfonyl chloride to form thealkylsulfonanilide derivative which may be treated directly with asuitable base in an inert reaction medium to effect ring closure.Although other bases such as phenyl lithium, butyl lithium and potassiumt butoxide may be employed in the above process, the alkali amides arepreferred.

This process may be diagrammed as follows:

X If, X l

NH RICH2SO2C1 NS 02CH2R1 Y D Y D base {inert reaction mediu wherein D isa reactive halide, R, R X and Y are groups which do not interfere withor partake in the reaction.

The 2,1benzisothiazoline-2,2-dioxides obtained by the describedprocesses may then be treated with either an a,,8-unsaturated nitrilesuch as acrylonitrile or Bmethylacrylonitrile, to form the cyanoethylderivative which provides a particularly useful starting material forthe preparation of other compounds, or an a,,8-unsaturated ketone suchas methyl vinyl ketone or methyl betamethylvinyl ketone to form thecompounds in which Z is COR.

The processes may be illustrated as follows:

i 02 Y I wherein R is other than hydrogen and all other symbols are asdescribed.

When R is hydrogen in the starting material, then the above additionreactions take place at both the 3 and the 3' positions.

The cyanoethyl derivatives may be used to prepare a Wide variety ofderivatives including cyanoalkyl derivatives in which the alkylene chainB is larger than ethylene. The alkylene chain can be built up treatingthe cyanoethyl derivative with a lower alkanol such as ethanol in thepresence of a suitable catalyst such as hydrochloric acid to form thecorresponding ethyl ester, treating that compound with lithium aluminumhydride to form the alcohol, treating the alcohol with tosyl chloride ina suitable solvent such as pyridine to form the tosylate, and finallytreating the tosylate with sodium cyanide to form the hitrile and, ifdesired, repeating the whole process to add another methylene group.

This process may be illustrated as follows:

B1 B-ON R1 B-CO2C H X X C2H5OH S02 HF $02 I N W Y Y i /LiA1H4 1/ R1 BCHOJI R1 BCH OTS X X TsCl S02 S02 pyridine N N Y l lNaCN R1 BCH CH X A IS02 Y in which all symbols represent groups which do not partake in orinterfere with the reaction.

The compounds in which Z is CO H may be prepared by treating a1,3-disubstituted-3-(2'-cyanoalkyl)-2,lbenzisothiazoline-Z,Z-dioxidewith a suitable base such as ethanolic potassium hydroxide, addingwater, refluxing the reaction mixture, removing the solvent, extractingwith 5 ether, acidifying the extracts and isolating the desiredcompound.

The described process may be diagrammed as follows:

R1 B-CN R BC O OH 7 7 KOI-I S 2 S02 Y wherein all symbols have theirassigned values and X and Y represent groups which do not partake in orinterfere with the reaction.

Representative of the compounds which may be prepared by the describedprocess are the following:

Those compounds in which Z is C(NOH)NH may be conveniently prepared byforming a mixture of hydroxylamine hydrochloride and sodium ethoxide inethanol under nitrogen, adding the appropriate nitrile to the mixture,refluxing the reaction mixture, and isolating the desired product.

The described process may be diagrammed as follows:

wherein all symbols have their assigned values and X and Y representgroups which do not partake in or interfere with the reaction.

Representative of the compounds which may be prepared by the describedprocess are the following:

1,3,-dimethyl 3(2'-hydroxyamidinoethyl)-2,l-benzisotriazoline-2,2-dioxide,

l-phenethyl 3 methyl-3-(2'-hydroxyamidinoethyl)-2,l-

benzisothiazoline-2,2-dioxide, and

l-cyclopentylmethyl 3methyl-3-(3'-hydroxyamidinopropyl)2,1benzisothiazoline-2,2-dioxide.

The compounds in which Z is CO R and wherein R is alkyl may beconveniently produced by preparing a solution of the appropriatenitrile, water, and an alkanol (e.g. ethanol), treating it with a streamof hydrogen chloride gas, and recovering the desired product byconventional means.

The described process may be diagrammed as follows:

R1 BCN R1 B-OOi-Rg X HCI I S02 I S02 N N Y Y wherein R is an alkyl of 1to 8 carbon atoms and all other symbols have their assigned values andrepresent groups which do not partake in or interfere with the reaction.

Representative of the compounds which may be prepared by the describedprocess are the following:

1,3-dimethyl 3 (2-carbethoxyethyl)-2,l-benzisothiazoline-2,2-dioxide,

1,3-dimethyl 3 (2-carbomethoxyethyl)-2,l-benzisothiazoline-2,2-dioxide,

l-phenethyl 3 methyl-3-(2-carbomethoxyethyl)-2,1-

benzisthiazoline-2,2-dioxide, and

l-cyclopentylmethyl 3methyl-3-(3carbobutoxypropyl)-2,1benzisothiazoline-2,2-dioxide.

The compounds in which Z is CONH CONHRg and CO R may be prepared bytreating the corresponding compounds in which Z is COOH with thionylchloride followed by treatment with either ammonia, an aminoalcohol oran amine.

The processes may be diagrammed as follows:

wherein R is not cyanoethyl and X and Y represent groups that do notpartake in or interfere with the reaction.

Representative of the compounds which may be prepared by the describedprocess are the following:

1,3-dimethyl 3 (2-carbamy1ethyl)-2,1-benzisothiazoline-2,2-dioxide,

l-phenethyl 3 methyl-3-(N,N-dimethyl-2'-carbamylethyl) 2,1benzisothiazoline-2,2-dioxide,

N-dimethylaminoethyl B-[3-(1,3 dimethyl)-2,1-benzisothiazolinyl]propionate-2,2-dioxide,

N-diethylaminoethyl B-[3-(3-methyl1-phenyl)-2,1-benzisothiazolinyl]propionate-2,2-dioxide,

N-dimethylaminoethyl-{fl-[3-( 1,3 dimethyl)-2,1-benzisothiazolinyl]}propionamide-2,2-dioxide, and

N-dimethylamidoethyl-{B [3 (cyclopropylmethyl 3-ethyl)-2,1-benzisothiazolinyl]}propionamide 2,2 dioxide.

The compounds in which X and Y are other than hydrogen are preferablyprepared by using conventional nitration, chlorination and the liketechniques, to place the ring substituent into thel-substituted-Z,1-benzisothiazoline-2, 2-dioxide. For example, chlorinemay be inserted into the 5 position by treating a1-substituted-2,l-benzisothiazoline-2,2-dioxide with N-chlorosuccinimidein dimethylformamide.

Acid addition salts of the compounds it the present invention may beconveniently prepared by contacting those compounds capable of formingsuch salts with a suitable acid such as formic acid, citric acid, maleicacid, sulfuric acid, hydrochloric acid, succinic acid, tartaric acid,benzoic acid or fumaric acid.

Quaternary ammonium salts may be formed by contacting those compoundscapable of forming such salts with a suitable alkylating agent such asdimethyl sulfate or an alkyl halide such as methyl chloride, methyliodide or ethyl bromide.

The thiocyanic acid addition salts of the compounds of this inventionwhen condensed with formaldehyde form resinous materials useful aspickling agents according to US. Pats. 2,425,320 and 2,606,155. Thecompounds also form fluosilicic acid addition salts which are useful asmoth proofing agents according to US. Pats. 1,915,334 and 2,075,359.

The novel compounds of the invention are pharmacologically active,especially the compounds 1,3-dimethyl- 3(2-cyanoethyl)2,1-benzisothiazoline-2,2-dioxide, 1,3 dimethyl 3(Z-carboxyethyl)2,1-benzisothiazoline-2,2- dioxide, 1,3 dimethyl 3-[(NdimethylarninoethyD-Z- carbamylethyl]2,1benzisothiazoline-Z,2-dioxideand 1- methyl 3,3 bis(2 cyanoethyl) 2,1-benzisothiazoline- 2,2-dioxidewhich have been shown at intravenous doses of about 10 mg./kg. to lowerblood pressure 10 to 40% in the standard vagotomized sodiumpentobarbital anesthetized dog preparation. The above compounds havealso been shown in mouse behavior studies to produce behavioral profilessimilar to those produced with known antihypertensive agents. The mousebehavior studies which also established that the compounds had LD inexcess of 200 mg./kg. intraperitoneally were conducted in accord withthe procedure outlined by S. Irwin in Animal and Clinical PharmacologicTechniques in Drug Evaluation, 1. H. Nodine and P. E. Siegler, Ed., YearBook Medical Publishers, Inc. 1964.

The following examples are presented to illustrate this invention:

EXAMPLE 1 oChloroethanesulfonanilide To a solution of 8 moles ofo-chloroaniline in 1.2 liters of toluene is added a solution of 514 g.(4 moles) of ethanesulfonyl chloride in 600 ml. of toluene over a 2- hr.period. The mixture is refluxed for 16 hrs., cooled, and filtered. Thefiltrate is washed thoroughly with 10% HCl and with saturated brine,dried, and evaporated. The crude residue is stirred with 5 liters of 10%NaOH for 3 hrs. After separation of the insoluble material, the aqueoussolution is acidified with concentrated HCl and cooled. The precipitateis filtered and dried to give 0- chloroethanesulfonanilide as astraw-colored powder, M.P. 46-49".

Analysis.Calcd. for C H ClNO S (percent): C, 43.74; H, 4.59; Cl, 16.14;S, 14.59. Found (percent): C, 43.81; H, 4.72; Cl 16.16; S, 14.69.

EXAMPLE 2 N-Methyl-o-chloroethanesulfonanilide To a solution of 550 g.(2.5 moles) of o-chloroethanesulfonanilide and 351 g. (6.25 moles) ofKOH in 3 liters of water is added 630 g. (5 moles) of dimethyl sulfate.The mixture is stirred at 70 for 6 hrs. and then cooled. The crudeproduct is taken up in chloroform, which is dried and evaporated.Distillation of the residue gives N-methyl chloroethanesulfonanilide asa colorless liquid, B.P. 120122 (0.05'mm.).

Analysis.-Calcd. for C H C1NO S (percent): C, 46.25; H, 5.18; C1, 15.17;S, 13.72. Found (percent): C, 46.36; H, 5.30; Cl, 15.22; S, 13.98.

EXAMPLE 3 1,3-dimethyl-2,1-benzisothiazoline-2,Z-dioxide A solution ofN-rnethyl-o-ch1oroethanesulfonanilide (23.4 g., 0.1 mole) in 40 ml. ofanhydrous ether is added dropwise to 0.35 mole of potassium amide in 1liter of liquid ammonia. After min., the reaction is quenched with 0.25mole of ammonium chloride, and the solvent allowed to evaporate. Theresidue is treated with 150 ml. of 10% HCl and 150 ml. of chloroform,which is separated, dried, and evaporated. Distillation of the residualliquid yields 1,3-dimethyl-2,l-benzisothiazoline- 2,2-dioxide as astraw-colored oil, B.P. 130132 (0.06 mm.).

Analysis.Calcd. for C H NO S (percent): C, 54.80; N, 7.13; S, 16.25.Found (percent): C, 55.05; H, 5.87; N, 7.15; S, 16.21.

EXAMPLE 4 1,3-dimethyl-3-(2-cyanoethyl)-2, 1-benziothiazoline2,2-dioxide To a cooled solution of 198 g. (0.1 mole) or 1,3-dimethyl2,1 benzisothiazoline 2,2-dioxide and 1 ml. of 30% methanolic potassiumhydroxide in 100 ml. of tertbutyl alcohol is added dropwise 5.8 g. (0.11mole) of acrylonitrile, and the cloudy solution stirred at roomtemperature for hours. The reaction mixture is acidified with 4 Nhydrochloric acid, diluted with 1.5 liters of water, and extracted withtwo 500-m1. portions of ether. The ether extracts are combined, dried,and evaporated. Elution of the residual oil from alumina with benzeneyields 1,3 dimethyl-3-(2-cyanoethyl)-2,1-benzisothiazoline-2,2-dioxidein the form of a straw-colored oil.

Arzalysis.Ca1cd. for C H N O S (percent): C, 57.58; H, 5.63; N, 11.19;S, 12.81. Found (percent): C, 57.81; H, 5.79; N, 10.92; S, 12.64.

EXAMPLE 5 1,3 -dimethy1-3 -(2'-carboxyethy1)-2,1-benzisothiazoline-2,2-dioxide To 15 g. (0.06 mole) of the nitrile of Example 4 is added100 ml. of potassium hydroxide-saturated ethanol, and the resultingmilky solution stirred at overnight. Water ml.) is added, and thesolution refluxed for 7 hours. Most of the solvent then is removed undervacuum, and the residue dissolved in 300 ml. of water. After twoextractions with ether ml.) and acidification with concentratedhydrochloric acid, the separated organic layer is taken up in ether,which is shaken with saturated brine, dried and evaporated.Recrystallization of the residual solid from chloroform-petroleum etherprovides the 1,3 -dimethyl-3-(2'-carboxyethy1)-2,1-benzisothiazoline aslight tan flakes, M.P. 126l82.

Analysis.--Calcd. for C H NO (percent): C, 53.53; H, 5.62; S, 11.91.Found (percent): C, 53.35; H, 5.51; S, 11.96.

EXAMPLE 6 1,3-dimethyl-3- 3 '-oxobutyl) -2,1-benzisothiazoline-2,2-dioxide A well-cooled solution of 5.9 g. (0.03 mole) of 1,3-dimethyl-2,1-benzisothiazoline-2,2dioxide and 0.6 g. of a 40% aqueoussolution of trimethylbenzyl ammonium hydroxide in 30 ml. of t-butylalcohol is treated dropwise with 3 g. (0.043 mole) of methyl vinylketone. The resulting amber solution is allowed to slowly warm to roomtemperature with stirring, then continued for a total of 43 hours. Afteracidification with 2 N sulfuric acid, the

reaction mixture is diluted with water (300 ml.) and extracted withthree -m1. portions of ether, which are combined, washed with saturatedbrine, and dried (N21 SO Solvent evaporation affords 10.6 g. of an amberliquid, which is eluted from 200 g. of silica gel with benzene-ether(3:1). The yellow oil thereby isolated is further purified byrechrornatography on 100 ml. of silica gel. Addition of dry ether tothis material brings about solidification, and the1,3-dimethyl-3-(3'-oxobutyl)- 2,1-benzisothiazoline-2,2-dioxide isobtained as a white powder, M.P. 7678.5.

Analysis.--Calcd. for C13H1'7N'O3S (percent): C, 58.40; H, 6.41; N,5.25. Found (percent): C, 58.38; H, 6.47; N, 5.48.

EXAMPLE 71,3-dimethyl-3-(2'-carbethoxyethyl)-2,1-benzisothiazoline-2,2-dioxide Asolution of 7.5 g. (0.03 mole) of the nitrile of Example 4 and 0.54 g.(0.03 mole) of water in ml. of absolute ethanol is stirred and treatedwith a stream of hydrogen chloride gas for 1 hour and filtered. Thefiltrate is evaporated to dryness, and the residual oil taken up inchloroform, washed with saturated sodium bicarbonate solution, then withsaturated brine, dried (Na SO and evaporated. Elution of the remainingmaterial from g. of silica gel with benzene ether yields1,3-dimethyl-3-(2'- carbethoxyethyl)-2,1-benzisothiazo1ine-2,2-dioxideas a pale yellow liquid.

Analysis.Calcd. for C H NO S (percent): C, 56.54; H, 6.42; N, 4.71.Found (percent): C, 55.78; H, 6.34; N, 5.08.

EXAMPLE 8 1,3-dimethyl-3-( 2-hydroxyamidinoethyl -2,l-benzisothiazoline-2,2-dioxide hydrochloride To a solution of 0.46 g.(0.02 g.-atom) of sodium in 40 ml. of absolute ethanol is added undernitrogen 1.4 g. (0.02 mole) of hydroxylamine hydrochloride. The mixtureis stirred for several minutes at room temperature, and then asuspension of 5.0 g. (0.02 mole) of the nitrile of Example 4 in 60 ml.of ethanol is added. The reaction mixture is refluxed for 6 hours,stirred overnight at 25, and then filtered. The filtrate is diluted withapproximately 300 ml. of ether, and the resulting hazy solution issaturated with hydrogen chloride gas. The deposited solid melts at199-200 with decomposition. Recrystallization from ethanol-ether yields1,3-dimethyl-3-(2'-hydroxyamidinoethyl)-2,1-benzis0thiazoline 2,2dioxide hydrochloride in the form of a tan powder, M.P. 200-201.

Analysis.Calcd. for C H C1N O S (percent): C, 45.07; H, 5.67; S, 10.03.Found (percent): C, 44.92; H, 5.77; S, 9.78.

EXAMPLE 91,3-dimethyl-3-(2-carbamy1ethy1)-2,1-benzisothiazoline-2,2-dioxide Asolution of 19.7 g. (0.10 mole) of 1,3-dimethyl-2,1-benzisothiazoline-2,2-dioxide and 2 ml. of 30% methanolic KOH in 100 ml.of t-butanol is treated portionwise with 7.8 g. (0.11 mole) ofacrylamide and then stirred at room temperature for 34 hours. Afterstanding an additional 33 hours, the reaction mixture is acidified with2 N H SO diluted with water (600 ml.), and extracted with three 125-m1.portions of ether, which are combined, dried (Na SO and evaporated.Recrystallization of the residual solid from chloroform-petroleum etheryields1,3-dimethyl-3-(2'-carbamylethyl)-2,1-benzisothiazoline-2,2-dioxide,M.P. 1l5117.

Analysis.Ca1cd. for C H N O S (percent): C, 53.73; H, 6.01; N, 10.44; S,11.94. Found (percent): C, 53.39; H, 5.89; N, 10.52; S, 11.54.

9 EXAMPLE 1o 1,3-dimethyl-3- [ethyldimethylaminoethyl)-2-carboxylate]2,1-benzisothiazoline-2,2-dioxide maleate Tht acidchloride, prepared from 5.4 g. (0.03 mole) of the related acid ofExample 5 and 7 g. of thionyl chloride in pyridine (0.03 mole)-benzene(75 ml.), in 50 ml. of dry benzene is added dropwise under nitrogen to acooled solution of dimethylaminoethanol (3.6 g., 0.04 mole) in benzene(25 ml.). The mixture is stirred at room temperature for 19 hours,extracted with two SO-ml. portions of 5% NaOH, dried, and evaporated.The residual oil is converted tol,3-dimethyl-3-[ethyl-(dimethylaminoethyl) 2'carboxylate]2,1-benzisothiazoline-2,2- dioxide maleatc, which isisolated as pale tan pellets, M.P. 108-111. A sample recrystallized fromethanolether melted at 110112.5.

Analysis.-Calcd. for C H N O S (percent): C, 52.63 H, 6.18; N, 6.14.'Found (percent): C, 52.72; H, 6.08; N, 6.43.

EXAMPLE 11 1,3-dimethyl-3 (N-dimethylaminoethyl) -2'-carbamylethyl] 2,1benzisothiazoline-2,2-dioxide To the acid chloride prepared from 5.4 g.(0.02 mole) of the appropriate acid in 75 ml. of dry benzene is added,under nitrogen and with cooling, a solution of dimethylaminoethylaminein 25 ml. of benzene. The resulting mixture is stirred overnight at 25then extracted twice with 5% NaOH, washed with saturated brine, dried,and evaporated. The residual oil is eluted from 230 g. of alumina withether to give 1,3-dimethyl-3-[(N-dimethylaminoethyl) 2'carbamylethyl]-2,1-benzisothiazoline- 2,2-dioxide as a colorless,viscous liquid.

Analysis.-Calcd. for C H N O S (percent): C, 56.61; H, 7.42; N, 12.38;S, 9.44. Found (percent): C, 55.88; H, 7.46; N, 12.30; S, 9.14.

EXAMPLE 12 1-methyl-3 ,3 bis(2-cyanoethyl)-2,1-benzisothiazoline-2,2-dioxide A solution of l-methyl 2,1 benzisothiazoline-2,2-dioxide(16.5 g., 0.09 mole) and 1 ml. of a 40% aqueous solution oftrimethylbenzyl ammonium hydroxide in 75 ml. of dioxane is cooled andtreated dropwise with 14.4 g. (0.27 mole) of acrylonitrile. The solutionis stirred overnight at 25 acidified with 1 N sulfuric acid, andevaporated under vacuum. The residue is taken up in chloroform, washedwith water, dried, and evaporated. Elution of the remaining 20.4 g. ofoil from 1 kg. of alumina with benzene-ether (2:1) gives some unchangedstarting material followed by the dinitrile as a yelloworange oil whichsolidified on standing. Recrystallization of the product fromchloroform-petroleum ether yields 1-methyl 3,3bis(2'-cyanoethyl)-2,1-benzisothiazoline- 2,2-dioxide in the form ofcream-colored granules, M.P. 100 101.5.

Analysis.Calcd. for C H N O S (percent): C, 58.11; H, 5.22; N, 14.52.Found (percent): C, 58.00; H, 5.08; N, 14.21.

EXAMPLE 13 1,3-dimethy1-5-chloro-2, 1benzisothiazoline-2,2-dioxide Asolution of 1,3-dimethyl 2,1 benzisothiazoline-2,2- dioxide (9.85 g.,0.05 mole) and 6.5 g. (0.05 mole) of N-chlorosuccinimide in 60 ml. ofdimethylformamide is heated at an oil bath temperature of 95 for 16hours. The cooled solution is diluted with water (600 ml.) and extractedwith two 125 ml. portions of ether, which are combined, shaken withsaturated brine, dried (Na SO and evaporated. The residual oil isdissolved in chloroform, which is heated with decolorizing charcoal,filtered, and evaporated. Elution of the remaining oil (10.8 g.) fromsilica gel (270 g.) with benzene-ether (8:1) yields a solid product.Recrystallization from cyclohexane-benzene (2:1) gives 1,3-dimethyl 5chloro 2,1 benziso- 10 thiazoline-2,2-dioxide in the form of whitecrystals, M.P. 7476.

Analysis.Calcd. for C H CINO S (percent): C, 46.65; H, 4.35; N, 6.05.Found (percent): C, 46.46; H, 4.17; N, 5.95.

EXAMPLE 141,3-dimethyl-3-(2-cyanoethyl)-5-ch1oro-2,1-benzisothiazoline-2,2-dioxideA solution of 1,3-dimethyl 5 chloro 2,1 benzisothiazoline-2,2-dioxide(4.8 g., 0.021 mole) in t-butanol (25 n1l.)-dioxane (10 ml.) is cooledand treated with 0.3 ml. of 30% methanolic KOH and then with 1.2 g.(0.023 mole) of acrylonitrile. Within a short time a precipitate forms,and the mixture is stirred at 25 for 24 hours. After neutralization with4 N HCl and dilution with 300 ml. of water, the solid is filtered anddried. The pale yellow powder melted at l01l02. Recrystallization frompetroleum ether-chloroform (1:1) gives 1,3-dimethyl-3- (2'-cyanoethyl) 5chloro 2,1 benzisothiazoline-2,2- dioxide in the form of small whiteflakes, M.P. 102-103.

Analysis.Calcd. for C H ClN O S (percent): C, 50.61; H, 4.60; N, 9.84.Found (percent): C, 50.34; H, 4.45; N, 9.79.

We claim:

1. A compound selected from compounds and pharmaceutically acceptablesalts of compounds of the formula in which X and Y are hydrogen,halogen, lower alkyl, nitro, lower alkoxy, benzyloxy or CF R is loweralkyl, phenyl or benzyl, R is hydrogen, lower alkyl or benzyl, B is analkylene of 2 to 6 carbon atoms, and Z is cyano, carboxy, carbamyl,carboxy-lower alkyl, COR,

CO R in which R is hydrogen or lower alkyl and COZNHRZ in which R isdimethylaminoethyl.

2. A compound of claim 1 in which X and Y are hydrogen, R is loweralkyl, phenyl or benzyl, R is hydrogen, lower alkyl or benzyl, and Z iscyano, carboxy, carbamyl, carboxy-lower alkyl, COR, -C(NOH)NH and -CO R3. A compound of claim 1 in which Y is hydrogen or chloro, R and R aremethyl, B is ethylene and Z is cyano.

4. A compound of claim 1 in which X and Y are hydrogen, R and R aremethyl, B is ethylene and Z is CO R in which R is hydrogen or ethyl.

5. A compound of claim 1 in which X and Y are hydrogen, R and R aremethyl, B is ethylene and Z is C(NOH)NH 6. A compound of claim 1 inwhich X and Y are hydrogen, R and R are lower alkyl, B is ethylene and Zis carboxy-lower alkyl.

7. A compound of claim 1 in which X and Y are hydrogen, R and R arelower alkyl, B is ethylene and Z is carbamyl.

References Cited Bunnet et al., Chem. Abstracts, 58: 1135lh (1963).Mustafa et al., Chem. Abstracts, 47: 1129b (1953).

ALEX MAZEL, Primary Examiner R. J. GALLAGHER, Assistant Examiner US. Cl.X.R. 260556, 999

